Pharmaceutical composition containing acid addition salt of basic drug

ABSTRACT

A pharmaceutical composition contains an acid addition salt of a basic drug and a fatty acid or bile acid. The acid addition salts thus formed exhibit enhanced transmucosal and transdermal penetration of the basic drug. The acid addition salts, an inclusion complex containing said salts and a use of said salts are also disclosed.

This application is a 371 of PCT/GB97/01873 filed Jul. 11, 1997.

BACKGROUND OF THE INVENTION

This invention relates to a pharmaceutical composition formulated fortransdermal or transmucosal delivery which contains as an activeingredient an acid addition salt of a basic drug and a fatty acid orbile acid, and to certain novel acid addition salts of basic drugs andfatty acids or bile acids.

The oral route of drug delivery is well established as the mostpreferred route of drug administration. However, when administered bythe oral route a drug enters the gastrointestinal tract where manytherapeutic agents are subjected to extensive presystemic elimination bygastrointestinal degradation and/or hepatic metabolism resulting inerratic or poor bioavailability. Further disadvantages of the oral routeare difficulty in swallowing medications especially by the elderly or inpaediatrics, or in the presence of nausea and vomiting.

Delivery of drugs via the oral, nasal, ocular, rectal or vaginal mucosaeor via the skin, offers a means of avoiding the disadvantages of theoral route as the drug reaches the systemic circulation directly. Themucosal route of drug delivery is a useful alternative to parenteraldelivery where rapid therapeutic effect is desired. The transermal routeis advantageous for sustained release of active ingredients.

There are several methods known in the art to deliver drugs to the oraland nasal mucosae [see Chien, Y W ed. Novel Drug Delivery Systems, 2ndEdition, Marcel Dekker 1992, pp 183-188, 244-249]. These include buccaland sublingual tablets or lozenges, adhesive patches, gels, solutions orsprays (powder, liquid or aerosol) for the oral cavity and solutions orsprays (powder, liquid or aerosol) for the nasal cavity. Suppositoriesand pessaries are well known galenical forms for rectal and vaginaldelivery, and sterile solutions, suspensions and ointments are similarlywell established forms for ocular delivery [The Pharmaceutical Codex12th Edition, The Pharmaceutical Press; Remington's PharmaceuticalSciences 18th Edition, Mack Publishing Company]. Transdermal drugdelivery has been extensively reviewed [Osborne, D W and Amann, A.Topical Drug Delivery Formulations, Marcel Dekker Inc.].

Relatively few drugs are currently administered via the mucosal anddermal routes due to problems associated with poor transport of thedrugs across mucosal or dermal membranes. A given drug will partitionbetween the lipid phase and the aqueous phase of biological membranesaccording to the lipophile/hydrophile balance of the drug molecule.According to pH partition theory, the permeation of an ionisablesubstance through biological membranes is dependent on the concentrationof the unionised species. Basic drugs, depending on their pKa, aregenerally ionized to varying extents at the pH of the mucosal surface,resulting in poor transmembrane permeation.

The absorption of drugs from biological membranes may be enhanced by (i)increasing drug solubility, (ii) pH modification to favour the unionizedform of the drug, (iii) addition of bioadhesive agents to improvecontact between the delivery system and the membrane and (iv)incorporation of so-called penetration enhancers.

There are a number of penetration enhancers known to influence thepermeability of drugs across biological membranes [for a recent reviewsee Walker, R B and Smith, E W Advanced Drug Delivery Reviews 1996, 18,295-301].

The mechanism by which sodium salts of medium chain fatty acids (C₆, C₈,C₁₀ and C₁₂) enhance the absorption of hydrophilic drugs acrossintestinal mucosa has been studied [Lindmark, T et al, J. Pharmacol.Exp. Ther. 1995, 275(2), 958-964.].

Oral absorption of antibiotics in U.S. Pat. No. 5,318,781 to Hoffmann-LaRoche is claimed to be enhanced by use of salts (e.g sodium) of capricor caprylic acids together with an anionic surfactant.

Transdermal formulations containing absorption accelerators teaching theuse of lauric acid diethanolamide salt is claimed in JP 05185371 toSekisui Chemical Company Limited.

The effects of sodium salts of bile acids, caprylic or capric acids asnasal drug absorption promoters have been reported. [Yamamoto, A et alInt. J. Pharm. 1993, 93(1-3), 91-99.].

Colonic absorption of cefmetazole and inulin are reported to beincreased by the use of sodium caprate, sodium laurate, and mixedmicelles composed of sodium oleate and sodium taurocholate [Tomita, M.et al, Pharm. Res. 1988, 5(6), 341-346.].

The promoting effect of sodium caprylate, sodium caprate and sodiumlaurate on rat nasal absorption of insulin has been reported [Mishima, Met al, J. Pharmacobio-Dyn 1987, 10(11), 624-631.].

WO 9524197 to Sekisui Chemical Company Limited, Japan; DainipponPharmaceutical Company Limited teaches a percutaneously absorbableplaster composed of a support and, formed on one side thereof, apressure-sensitive adhesive layer comprising a pressure-sensitiveadhesive, a drug and a percutaneous absorption accelerator.

Skin penetration enhancement using free base and acid addition saltcombinations of active agents are described in EP 321870 to TheratechInc. Compositions for topical application were prepared containingactive pharmaceutical permeants capable of existing in both free baseand acid addition salt form. The acids used included HCl, tartrate,sulphate, HBr, mesylate and maleate.

A fatty acid salt of propranolol as an alternative to polymericformulations was investigated for possible use in sustained-release oralformulations and evaluated in dogs. An increase in bioavailability wasobserved after propranolol laurate was administered. [Aungst, B J;Hussain, M A, Pharm. Res. 1992,9(11), 1507-9.].

In an article in J. Pharm. Sci (1990), 79(12), 1065-1071 by T Ogiso andM Shintani the effects of a series of fatty acids including lauric acidand myristic acid on the percutaneous absorption of propranolol wasexamined. The results indicate that a significant proportion ofpropranolol will penetrate across the stratum corneum by forming acomplex with a fatty acid, and that the complex will dissociate to eachcomponent in the interface between the corneum and a viable epidermis,where propranolol partitions into this water-rich tissue.

In an article in Chem. Pharm. Bull. (1991), 39 (10), 2657-2661 by TOgiso et al, there is reported that propranolol suppositories withlauric acid at various molar ratios were administered to the rat rectum.Propranolol absorption from Witespol and macrogol suppositories withlauric acid at a 1:1 molar ratio was much larger than that afterpropranolol alone. The results supported the concept that a portion ofpropranolol, by forming a 1:1 complex with lauric acid, would penetrateacross the rectal mucosa more easily than propranolol alone.

In an article in Pharm. Res. (1989), 6(7), 628-632 by P G Green et al,it is disclosed that the lipophilicity of cationic drugs can beincreased by forming ion pairs with the carboxylate anion of fattyacids. Transport of cations across an iso-Pr myristate membrane wasfacilitated in the presence of oleic acid, and lauric acid, providing anappropriate pH gradient existed.

Slowly dissolving albuterol salts prepared with adipic and stearic acidshave been investigated as a potential means of extending the duration ofaction of the drug following aerosol delivery to the lung [Jashnani, Ret al, J. Pharm. Sci. 1993, 82(6), 613-16.].

From the above prior art it is evident that enhancement of penetrationof active agents through the skin, intestinal, oral, nasal or rectalmucosa has been effected by incorporation of fatty acids or bile acidspresent as the free acid or usually as the sodium salt at a givenconcentration in a pharmaceutical composition containing an activeagent, present as free acid or free base, or as a simplepharmaceutically acceptable salt. Little attention has been paid tomeans of manipulating the active agents per se to attain enhancedpenetration through the membrane barrier.

Cyclodextrins and their derivatives have found extensive application assolubilizers and stabilizers due to their ability to form inclusioncomplexes with a wide variety of compounds [see (J Szejtli, CyclodextrinTechnology, Kluwer Academic Press) and (J Szejtli & K-H Fromming,Cyclodextrins in Pharmacy, Kluwer Academic Press)]. Cyclodextrins havebeen used to enhance intestinal absorption of drugs primarily throughincreasing solubility. Recently, cyclodextrins have been shown to havepositive and negative effects on transdermal penetration of drugs [see(Loftsson, T et al, International Journal of Pharmaceutics 1995, 115,255-258), (Vollmer, U et al, International Journal of Pharmaceutics1993, 99, 51-58), (Legendre, J Y et al, European Journal ofPharmaceutical Sciences 1995, 3, 311-322) and (Vollmer, U et al, Journalof Pharmacy and Pharmacology 1994, 46, 19-22)]. Cyclodextrins mayimprove nasal absorption of drugs [see (Merkus, F W et al,Pharmaceutical Research 1991, 8, 588-592) and (Shao, Z et al,Pharmaceutical Research 1992, 9, 1157-1163)] and enhance absorption fromsublingual administration of drug/cyclodextrin complexes [Behrouz, S etal, Journal of Clinical Endocrinology and Metabolism 1995, 80,3567-3575]. Cyclodextrins also protect nasal mucosal damage bypenetration enhancers [see Jabbal-Gill, I et al, European Journal ofPharmaceutical Sciences 1994, 1(5), 229-236].

Cyclodextrins are water soluble cone-shaped cyclic oligosaccharidescontaining 6, 7 or 8 glucopyranose units. The interior or “cavity” ofthe cone is hydrophobic whilst the exterior is hydrophilic. The size ofthe cavity increases with increasing number of glucose units. Severalcyclodextrin derivatives such as alkyl, hydroxyalkyl and sulfoalkylethers have been prepared with improved solubility [see (J Szejtli & K-HFromming, Cyclodextrins in Pharmacy, Kluwer Academic Press) and (Stella,V J et al, Pharmaceutical Research 1995, 12 (9) S205)].

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided apharmaceutical composition formulated for transdermal or transmucosaldelivery comprising as an active ingredient a compound of the formula I:

B⁺RCOO⁻

wherein B⁺ is a cation of a basic drug, and RCOO⁻ is an anion of a bileacid, together with one or more excipients for transdermal ortransmucosal delivery.

According to a second aspect of the invention there is provided acompound of the formula I:

B⁺RCOO⁻

wherein B⁺ is a cation of a basic drug and RCOO⁻ an anion of a bileacid.

According to a third aspect of the invention there is provided the useof a compound of the formula I:

B⁺RCOO⁻

wherein B⁺ is a cation of a basic drug, and RCOO⁻ is an anion of a bileacid, together with one or more excipients for transdermal ortransmucosal delivery, in the manufacture of a medicament fortransmucosal or transdermal delivery.

According to a fourth aspect of the invention there is provided apharmaceutical composition formulated for transdermal or transmucosaldelivery comprising as an active ingredient a compound selected from thegroup consisting of sumatriptan caprate, sumatriptan laurate,sumatriptan glycodeoxycholate, salbutamol laurate, salbutamol caprate,salbutarnol glycodeoxycholate, codeine caprate, codeine laurate,loperamide glycodeoxycholate, sumatriptan caprate cyclodextrin complex,salbutamol caprate cyclodextrin complex, and salbutamolglycodeoxycholate cyclodextrin complex, together with one or moreexcipients for transdermal or transmucosal delivery.

DESCRIPTION OF EMBODIMENTS

The first aspect of the invention is a pharmaceutical compositionformulated for transdermal or preferably transmucosal deliverycomprising as an active ingredient a compound of the formula I:

B⁺RCCO⁻

wherein B⁺ is a cation of a basic drug, and RCOO⁻ is an anion of a bileacid, together with one or more excipients for transdermal ortransmucosal delivery.

By a “basic drug” there is meant a drug which contains one or moreprotonable functionalities. Suitable drugs are set out in the Tablebelow. Those marked with an * are preferred.

CLASS EXAMPLES Analgesics (opioids) and codeine* derivatives morphine*benzylmorphine propoxyphene methadone pentazocine sufenatanil alfentanilfentanyl* pethidine butorphanol buprenorphine diamorphine dihydrocodeinedypyrone oxycodone dipipanone alphaprodine levorphanol dextromoramidehydromorphone nalbuphine oxymorphone hydrocodone (nalorphine -antagonist) (naloxone - antagonist) Antimicrobials Quinolonesnorfloxacin ciprofloxacin lomefloxacin balofioxacin ofloxacinsparfloxacin tosufloxacin temafloxacin clinafloxacin perfloxacintosufloxacin enoxacin amifloxacin fleroxacin Aminoglycosidesstreptomycin amikacin gentamicin tobramycin neomycin josamycinspectinomycin kanamycin framycetin paromomycin sissomycin viomycinGlycopeptides vancomycin Lincosamides clindamycin lincomycinPenicillins, cephalosporins and cefepime related β-lactams cefmenoximecefotiam cephalexin bacampicillin lenampicillin pivampicillintalampicillin Macrolides erythromycin oleandomycin Tetracyclinestetracycline minocycline rolitetracycline methacycline meclocyclineAntimycobacterials isoniazid pyrimethamine ethambutol Antiviralsacyclovir saquinavir indinavir ganciclovir amantadine moroxydinerimantidine famciclovir zalcitabine cidofovir valacyclovir lamivudinenevirapine Antiprotozoals metronidazole temidazole pentamidine mepacrinecarnidazole robenidine emetine dihydroemetine halofuginone homidiummelarsoprol Antiseptics aminacrine Antifungals ketoconazole itraconazolemiconazole econazole clotrimazole amphotericin B butoconazolechlormidazole croconazole diamthazole fenticonazole nystatin cloconazoleeconazole miconazole tioconazole Anti-depressants clomipramine (allclasses) lofepramine phenelzine tranylcypromine dothiepin nortryptalineamitryptaline imipramine mianserin maprotiline desipramine trazodonefluoxetine trimipramine citalopram doxepin fluvoxamine lofepraminenomifensine paroxetine Anti-diabetics glipizide metformin phenforminAnti-convulsants carbamazepine ethosuxamide diphenylhydantoinphenytoin(−OH) primidone methsuximide Anticholinergics atropine(antimuscarinics) benztropine (all classes) scopolamine homatropinehyoscine hyoscyamine orphenadrine pirenzipine procyclidine telenzipinepropantheline dicyclomine biperiden trihexphenidyl oxybutinin benzhexolbiperiden ipratropium pipenzolate mepenzolate cyclopentolateAnthelminitics albendazole mebendazole flubendazole fenbendazolepyrantel ivermectin Antigout allopurinol colchicine Antihistamines andchlorpheniramine phenothiazines dimenhydrinate (all classes) hydroxyzinediphenhydramine bromodiphenhydramine astemizole loratidine acepromazinethioridazine brompheniramine carbinoxamine chlorcyclizine chloropyraminechlorphentermine chlorprothixene dexchlorpheniramine antazolineazatidine azalastine clemastine clemizole cyroheptadine diphenylpyralinedoxylamine flunarizine mequitazine meclozine mepyramine pheniramineterfenadine triprolidine trimeprazine ebastine cinnarizineAnti-migraines ergotamine dihydroergotamine methysergide sumatriptan*naritriptan almotriptan zolmitriptan* rizatriptan* eletriptanflumedroxone pizotifen Anti-tussives and dextromethorphan mucolyticspholcodeine acetylcysteine noscapine Antineoplastics and azathiprineImmunosupressants methyluracil fluorouracil vincristine vinblastinemelphalan cyclophosphamide aminoglutethimide mercaptopurine tamoxifenchlorambucil daunorubicin mechlorethamine doxorubicin Anti-malarialsquinine chloroquine pyrimethamine amodiaquine piperaquine proguanilchloroproguanil mefloquine primaquine halofantrine Anxiolytics,Sedatives, bromazepam Hypnotics, Antipsycotics nitrazepam diazepamoxazepam Benzodiazepines clonazepam chlorazepate lorazepam midazolamtriazolam flunitrazepam Butyrophenones droperidol haloperidolBarbiturates allobarbitone aprobarbitone phenobarbitone amylobarbitonebarbitone butobarbitone Other zopiclone hydroxyzine buspironetandospirone Bronchodilators (other) theophylline Cardiovascular Drugsacebutatol a) β-Blockers alprenolol atenolol labetalol metopralolnadolol timolol propanolol pindolol tolamolol sotalol oxprenololbunitrolol carazolol indenolol b) Anti-arrythmics/ disopyramidecardiotonics mexilitine tocainide aprindine procainamide quinidinedobutamine c) Ca channel blockers verapamil* (all classes) diltiazemamlodipine felodipine nicardipine* gallopamil prenylamine c)Antihypertensives/ diazoxide Vasodilators guanethidine clonidinehydralizine dihydralizine minoxidil prazosin phenoxybenzamine reserpinephentolamine perhexiline indapamide debrisoquine bamethan bethanidinedobutamine indoramin d) Ace inhibitors captopril* enalapril* lisinoprilramipril* imidapril CNS stimulants/ methylphenidate anorecticsfenfluramine amphetamine methamphetamine bemegride caffeinedexamphetamine chlorphentamine fencamfamine prolintane Diureticsfurosemide acetazolamide amiloride triampterene bendrofluazidechlorothiazide chlorthalidone cyclothiazide hydroflumethiazidehydrochlorothiazide hydroflumethiazide Gatrointestinal Agents a)Motility enhancers, domperidone modulators and metoclopramide*anti-emetics cisapride prochlorperazine pirenzipine cinitapridecyclizine* chlorpromazine prochloperazine promethazine c) Acid secretionmodulators cimetidine ranitidine famotidine omeprazole nizatidine d)Anti-diarrhoels loperamide* diphenoxylate* e) Emetics apomorphine Musclerelaxants chlorzoxazon rocuronium suxamethonium vecuronium atracuriumfazadinium doxacurium mivacurium pancuronium tubocurarine pipecuriumdecamethonium tizanidine piridinol succinylcholine Cholinergic Agentsacetylcholine benzpyrinium edrophonium physostigmine neostigminepyridostygmine β-adrenergic agonists adrenaline ephedrinepseudo-ephedrine amidephrine oxymetazoline xylometazoline terbutaline*salbutamol* salmeterol* phenylpropanolamine cyclopentamine phenylephrineisoproterenol fenoterol* xamoterol Other CNS active agents dopaminelevodopa Endocrine agents bromocriptine propylthiouracil Localanaesthetics lidocaine (lignocaine)* procaine* amethocaine bupivacaine*butacaine oxybuprocaine mepivacaine cocaine prilocaine amylocainechloroprocaine cinchocaine etidocaine propoxycaine tropacocaineMiscellaneous Mydriatics cyclopentolate Antiglaucoma methazolamidedorzolamide acetazolamide Opioid peptides dynorphins* enkephalinsPeptides oxytocin vasopressin

Preferred drugs include sumatriptan, salbutamol (also known asalbuterol), codeine, and loperamide.

The invention also includes a pharmaceutical composition formulated fortransdermal or transmucosal delivery comprising as an active ingredienta compound selected from the group consisting of sumatriptan caprate,sumatriptan laurate, sumatriptan glycodeoxycholate, salbutamol laurate,salbutamol caprate, salbutamol glycodeoxycholate, codeine caprate,codeine laurate, loperamide glycodeoxycholate, sumatriptan capratecyclodextrin complex, salbutamol caprate cyclodextrin complex, andsalbutamol glycodeoxycholate cyclodextrin complex, together with one ormore excipients for transdermal or transmucosal delivery.

The monocarboxylic fatty acids for use in the present invention, namely

C₁₀—capric acid CH₃(CH₂)₈COOH; and

C₁₂—lauric acid CH₃(CH₂)₁₀COOH

may be manufactured from fats and oils derived from edible sources whichare approved by the Food and Drug Administration (CFR 21 172.860).

The bile acids include all monobasic carboxylic acids derived from bileand include: glycocholic acid, glycodeoxycholic acid, cholic acid,deoxycholic acid, taurocholic acid, and taurodexycholic acid.

The preferred anions for use with the preferred basic drugs listed aboveare glycodeoxycholate anions.

In terms of the invention, an acid addition salt in solid, isolatedform, is formed between the cation of the basic drug and the anion ofthe fatty acid or bile acid.

The fatty acids and bile acids are known as penetration enhancers, i.ecompounds which alter the membrane as a barrier or otherwise increasethe flux of a desired drug across the barrier. The formation of theseacid addition salts enhances the transmucosal and transdermalpenetration of the basic drugs.

By the terms “mucosal” or “mucosa” or “mucosae” is meant the epithelialmembranes lining the oral, nasal, rectal, vaginal and ocular cavities.

By the term “dermal” or “skin” is meant any skin surface.

The fatty acid and bile acid addition salts of pharmaceutically activeagents or drugs according to the invention are characterised by arelatively low aqueous solubility. The salts may be prepared by anyconventional means such as dissolving the free base of the drug in asuitable solvent such as a lower alcohol, preferably methanol or ethanolpreviously dehydrated to give a half saturated solution, to which isadded 1 mol equivalent of either fatty or bile acid with stirring. Theresulting solution may be heated to between 40-60° C. for one to severalhours. The solvent is removed by rotary evaporation under vacuum anddried at elevated temperature in vacuo to constant weight.Alternatively, the sodium salt of the fatty acid or bile acid isdissolved in water at elevated temperature. A solution of thecommercially available salt of the drug (e.g hydrochloride, sulphate,succinate, phosphate, etc) is added slowly with stirring at elevatedtemperature. The resulting solution is cooled to room temperature andthe addition salt precipitate collected on a filter, washed with coldwater and dried in vacuo.

The aqueous solubility of the fatty acid or bile acid addition salt ofthe drug may be increased by complexation with a cyclodextrin. Thecyclodextrin may be α, β or γ-cyclodextrin or derivative thereof.Cyclodextrin inclusion complexes may be prepared on the basis of liquidstate, solid state or semi-solid state reaction between the components(J Szeitli, Cyclodextrin Technology, Kluwer Academic Press). Theinclusion complex may be prepared by conventional means such as kneading1:1 mol/mol quantities of the salt and cyclodextrin in the presence of asmall amount of water to produce a uniform paste. The mixture isvigorously kneaded for 0.25-4 hours and then dried under vacuum atelevated temperature. The product obtained is characterised by anincrease in drug water solubility at 25° C. relative to the freeuncomplexed acid addition salt.

A preferred pharmaceutical composition of the invention is a sublingualtablet containing a therapeutic dose of a basic drug in the form of afatty acid or bile acid addition salt present as a cyclodextrininclusion complex capable of rapid dissolution. Preferred compounds forsublingual administration include drugs from therapeutic categorieswhere rapid therapeutic response is required or where limitations areimposed by conventional delivery (analgesics, anti-migraine,anti-emetic, anxiolytics, anti-diarreals, anti-arrythmics,anti-hypertensives, anti-anginals, anti-asthmatics, hormones,peptide-based pharmaceuticals). The composition may contain additionalpermeation enhancers such as laurocapram or sodium dodecyl sulphate.Conventional excipients such as binders (microcrystalline cellulose),disintegrants (sodium carboxymethyl cellulose), buffers (tromethamine,sodium bicarbonate, sodium carbonate) flavours, lubricants (magnesiumstearate, sodium stearyl fumarate) and organopletic modifying agents(xylitol) may be added in suitable quantities. The excipients with theexception of flavours and lubricant, are granulated together with thecomplex and dried. The dried granulate is sieved together with thelubricant and flavour and mixed. The mixture is compressed at 20-50Ninto sublingual tablets.

The acid addition salt present in part or completely as a cyclodextrininclusion complex may be formulated together with conventionalpharmaceutical excipients into sustained release buccal tablets orpatches with uni-directional release according to methods known in theart. Preferred excipients for sustained release buccal tablets orpatches are muco-adhesive polymers such as cross-linked polyacrylicacids (carbomers, polycarbophils).

The acid addition salt or the water soluble cyclodextrin complex of theacid addition salt may be formulated as drops, spray or gel for buccalor sublingual administration according to methods known in the art.Preferred excipients include viscosity modifying agents (e.ghydroxypropylmethylcellulose, carbomers, polycarbophils, chitosans, guargum, alginates), flavours, buffers (tromethamine, sodium bicarbonate,sodium carbonate), preservatives (bronopol, benzalkonium chloride, EDTA,chlorhexidine gluconate) and anti-oxidants (N-acetyl-cysteine, sodiumsulfite, sodium metabisulfite).

The acid addition salt or the water soluble cyclodextrin inclusioncomplex of the salt may be formulated as a powder insufflation or fornasal administration according to conventional methods. Preferredexcipients include muco-adhesive polymers to enhance residence time (e.gcarbomers, polycarbophils, chitosans).

The water soluble cyclodextrin inclusion complex of the salt may beformulated as an aqueous nasal spray according to methods appreciated inthe art. Preferred excipients include muco-adhesive polymers to enhanceresidence time (e.g carbomers, polycarbophils, chitosans), viscositymodifying agents (alkylcelluloses, hydroxyalkylcelluloses,hydroxypropylmethylcellulose, carbomers, polycarbophils, chitosans, guargum, alginates, buffers (tromethamine, sodium bicarbonate, sodiumcarbonate), preservatives (bronopol, benzalkonium chloride, EDTA,chlorhexidine gluconate) and anti-oxidants (N-acetyl-cysteine, sodiumsulfite, sodium metabisulfite).

The acid addition salt or the water soluble cyclodextrin inclusioncomplex of the acid addition salt may be formulated for rectaladministration as a suppository according to conventional methods.

The acid addition salt or the water soluble cyclodextrin inclusioncomplex of the acid addition salt may be formulated for vaginaladministration as a pessary according to conventional methods.

The acid addition salt may be formulated for ocular administration as aneye ointment according to conventional methods.

The acid addition salt or the water soluble cyclodextrin inclusioncomplex of the salt may be formulated for ocular administration aseye-drops according to conventional methods.

The general principles of formulation and manufacture of sublingual,buccal, nasal, rectal, vaginal and ocular pharmaceutical compositionsmay be found in The Pharmaceutical Codex 12th Edition. ThePharmaceutical Press; Remington's Pharmaceutical Sciences 18th Edition,Mack Publishing Company. Transdermal pharmaceutical compositions havebeen extensively reviewed [Osborne, D. W and Amann, A. topical DrugDelivery Formulations, Marcel Dekker Inc.].

The invention encompasses the use of a broad range of pharmaceuticallyactive agents which are capable of forming acid addition salts withfatty acids or bile acids. The compositions of this invention may beutilized in delivering the pharmaceutically active agent to thefollowing target areas: (1) the sublingual surface or floor of mouth,(2) the buccal cavity, (3) the gums, (4) the nasal passages, (5) therectum or colon, (6) the vagina, (7) the ocular cavity or cul-de-sac ofthe eye, and (8) the skin.

The preferred pharmaceutical forms are sublingual tablets, nasal sprays,buccal tablets, suppositories (rectal and vaginal), transdermal patchesand topical gels.

Examples of the invention will now be given.

EXAMPLE 1

Sumatriptan base ((2.29g; 7.75 mmol) was dissolved in boiling ethylacetate (300 mL) with stirring. Capric acid (1.33 g; 7.75 mmol) wasdissolved in ethyl acetate (10 mL) and added to the sumatriptan basesolution in one portion. The hot solution was stirred for a further 10minutes and allowed to cool to room temperature. Evaporation of thesolvent by rotary evaporation rave a pale yellow oil. Hexane (50 mL) wasadded and a white precipitate formed that was filtered off under vacuum.The precipitate was washed with hexane and allowed to dry at roomtemperature to give sumatriptan caprate as a pale yellow solid (2.79 g;77.4%). The sumatriptan caprate was characterised by DSC and FT-IR. DSCgave a single, sharp endotherm with the onset at 94.6° C. The FT-IRdiffered significantly from that of the sumatriptan base.

EXAMPLE 2

Salbutamol base (13.91 g; 58.13 mmol) was dissolved in ethanol (600 mL,96%) with magnetic stirring to give a pale yellow liquid. Capric acid(10.01 g; 58.11 mmol) was added with vigorous stirring which wascontinued until all solid material had dissolved. The solvent wasremoved by rotary-evaporation to give a pale yellow tacky semi-solid.This was dissolved in warm ethyl acetate (300 mL), then stored at 5° C.for 36 hours, resulting in the precipitation of a fine white solid. Themother liquor was removed by vacuum filtration, and the precipitatewashed with cold ethyl acetate. Any remaining solvent was removed bystoring the precipitate at 35° C. and 0 bar pressure for 6 hours.Salbutamol caprate was obtained as a white solid (18.93 g; 79.13%).Moisture content K.F. 0.32%; melting point 99.4° C. (onset of endothermin DCS thermogram). The theoretical percentage of salbutamol base insalbutamol caprate is 58.14%. Experimentally the percentage salbutamolbase in salbutamol caprate was found to be 56.42%. The pH of a saturatedaqueous solution is 7.24. The aqueous solubility is 4.76 mg/mL.

EXAMPLE 3

Salbutamol base (4.00 g; 16.72 mmol) was dissolved in ethanol (200 mL;99.7-100%), to which was added lauric acid (3.681 g; 18.39 mmol; 10%molar excess relative to salbutamol base) and dissolved. A pale yellowsolution was formed. Removal of the ethanol by rotary-evaporation gave aviscous, pale yellow residue. The residue was redissolved in ethylacetate (10 mL) by gentle heating on a water bath (60° C.). The solutionwas placed in a fridge overnight. A white precipitate formed which wasisolated by vacuum filtration and washed with 10 mL cold ethyl acetate.The precipitate was dried further in a vacuum oven at 40° C. for 16hours. This gave salbutamol laurate as a white powder (6.6461 g; 86.5%yield). Melting point was found to be 104° C. (onset of endotherm in DSCthermogram). Theoretically salbutamol laurate contains 54.43% m/msalbutamol base.

EXAMPLE 4

Salbutamol base (1.2007 g; 5.02 mmol) was dissolved in ethanol (100 mL)with vigorous stirring. Glycodeoxycholic acid (2.4601 g; water content:4.25% w/w; 5.25 mmol˜5% molar excess) was added and dissolved withstirring. A clear, colourless solution was obtained. The ethanol wasremoved by vacuum rotary-evaporation to give a viscous, yellow residue.Ethyl acetate (200 mL) was added to the residue and the mixture heatedin a water bath with constant agitation. As the yellow residuedissolved, a white precipitate formed. Agitation was continued until theyellow residue disappeared. The ethyl acetate solution was cooled in anice bath. The precipitate was isolated by vacuum filtration and dried ina vacuum oven at 40° C. for 20 hours to give salbutamolglycodeoxycholate (3.662 g; water content; 4.95% w/w; % yield; 97.9%).Analysis by differential scanning calorimetry from 50 to 200° C. gave nosignificant thermal event. Slow decomposition was evident after 110° C.A saturated aqueous solution gave a pH of 6.12. The aqueous solubilitywas greater than 8.35 mg/mL. The theoretical percentage of salbutamolbase in the salbutamol glycodeoxycholate 34.74%.

EXAMPLE 5

Codeine base (4.0016 g; 12.60 mmol) was dissolved in ethanol (100 ml).Capric acid (2.3902 g; 13.86 mmol) was added and dissolved withstirring. The ethanol was removed under vacuum. The residue wasredispersed in ethyl acetate (25 mL) which was then removed undervacuum, and the residue redissolved in ethyl acetate (10 mL) withheating on a water bath (60° C.). The ethyl acetate solution was placedin a fridge for 16 hours to yield a white precipitate which was isolatedby vacuum filtration and washed with cold ethyl acetate (20 mL). Thisprecipitate proved to be very deliquescent, and on standing became aviscous, clear mass. This mass was redissolved in ethyl acetate (200mL), the solvent was evaporated to give a viscous yellow residue. Thisresidue was stored at 8° C. for 48 hours to give a pale yellow solid.This solid was dried under vacuum (0 bar) at 25° C. This yielded codeinecaprate as a pale yellow solid (5.7301 g; 89.6% yield). The material wasanalysed by Differential Scanning Calorimetry in order to determine themelting point. However, thermal analysis from 50 to 200° C. showed nothermal event.

EXAMPLE 6

Codeine base (4.0002 g; 12.60 mmol) was dissolved in ethanol (100 mL;99.7-100%) with stirring. Lauric acid (2.7822 g; 13.86 mmol; 10% excessrelative to codeine base) was dissolved in the ethanol/codeine solution.The resulting solution was stirred for 5 minutes. The ethanol wasremoved by rotary-evaporation to give a pale yellow residue. The residuewas redispersed in ethyl acetate (10 mL) by heating on a water bath (60°C.). Once all the material had redissolved the solution was placed at 4°C. for 16 hours. A white precipitate formed which was isolated by vacuumfiltration. The precipitate was dried further in a vacuum oven for 16hours at 40° C. to give codeine laurate (2.4757 g; 36.50%). The materialwas analysed by Differential Scanning Calorimetry in order to determinethe melting point. However, thermal analysis from 50 to 200° C. showedno thermal event.

EXAMPLE 7

Sodium glycodeoxycholate (0.1211 g;˜0.24 mmol) was dissolved in hot (80°C.) deionized water (50 mL). Loperamide HCl was dissolved in hot (80°C.) deionized water (100 mL). The loperamide HCl solution was addeddropwise to the sodium glycodeoxycholate solution which stirring at 80°C. Immediately upon addition of the loperamide HCl solution a whiteprecipitate was formed. After addition of the loperamide HCl solution,the resulting suspension was stirred for 5 minutes at 80° C. Thissuspension was allowed to cool to room temperature, then filteredthrough filter paper (Whatman No 5) under vacuum. The precipitate wasdried further in a vacuum oven at 40° C. for 16 hours. This gave a whitepowder (0.0771 g; 34.36°). Analysis by Differential Scanning Calorimetryto obtain a melting point yielded no thermal event from 50 to 250° C.

EXAMPLE 8

Sumatriptan caprate and hydroxypropyl-beta cyclodextrin (HPB) werecomplexed by the kneading method. Sumatriptan caprate (1.254 g) and HPB(3.748 g) were blended together. Water (4.5 mL) was added and themixture ground together in a mortar with a pestle to form a uniformpaste. Grinding was continued for 30 minutes. The paste was then driedin a vacuum oven (40° C.; 0 bar) for 48 hours. The solid mass was brokenup, passed through a 60 mesh screen and returned to the vacuum oven (40°C.; 0 bar) for 12 hours in order to ensure uniform drying of thecomplex. Analysis by HPLC for sumatriptan base content, and Karl Fischerfor moisture content gave the following results: % sumatriptan base was16.40% and the moisture content was 3.45%. The complex was characterisedby DSC, FT-IR and XRD.

EXAMPLE 9

Sumatriptan caprate and gamma-cyclodextrin was complexed by the kneadingmethod. Sumatriptan caprate (1.325 g) and gamma-cyclodextrin (3.675 g)were blended together. Water (6 mL) was added and the mixture groundtogether in a mortar with a pestle to form a uniform paste. Grinding wascontinued for 30 minutes. The paste was then dried in a vacuum oven (40°C.; 0 bar) for 48 hours. The solid mass was broken up, passed through a60 mesh screen and returned to the vacuum oven (40° C.; 0 bar) for 12hours in order to ensure uniform drying of the complex. Analysis by HPLCfor sumatriptan base content, and Karl Fischer for moisture content gavethe following results: % sumatriptan base was 16.78% and the moisturecontent was 6.80%. The complex was characterised by DSC, FT-IR and XRD.

EXAMPLE 10

Salbutamol caprate and hydroxypropyl-beta cyclodextrin (HBP) werecomplexed by the kneading method. Salbutamol caprate (2.72 g) and HPB(7.728 g) were blended together. Water (5 mL) was added and the mixtureground together in a mortar with a pestle to form a uniform paste.Grinding was continued for 30 minutes. The paste was then dried in avacuum oven (40° C.; 0 bar) for 48 hours. The solid mass was broken up,passed through a 60 mesh screen and returned to the vacuum oven (40° C.;0 bar) for 12 hours in order to ensure uniform drying of the complex.Analysis of HPLC for salbutamol base content, and Karl Fischer formoisture content gave the following) results: % salbutamol base was12.97%, and the moisture content was 5.56%. The complex wascharacterised by DSC, FT-IR and XRD. The solubility in aqueous solutionwas greater than 4.8 mg/mL, and the pH of a saturated aqueous solutionwas 6.79.

EXAMPLE 11

Salbutamol caprate and gamma-cyclodextrin were complexed by the kneadingmethod. Salbutamol caprate (2.409 g) and gamma-cyclodextrin (7.591 g)were blended together. Water (12 mL) was added and the mixture groundtogether in a mortar with a pestle to form a uniform paste. Grinding wascontinued for 30 minutes. The paste was then dried in a vacuum oven (40°C.; 0 bar) for 48 hours. The solid mass was broken up, passed through a60 mesh screen and returned to the vacuum oven (40° C.; 0 bar) for 12hours in order to ensure uniform drying of the complex. Analysis by HPLCfor salbutamol base content, and Karl Fischer for moisture content gavethe following results: % salbutamol base was 12.83%, and the moisturecontent was 7.92%. The complex was characterised by DSC, FT-IR and XRD.The solubility in aqueous solution was 3.2 mg/mL, and the pH of asaturated aqueous solution was 7.00.

EXAMPLE 12

Codeine laurate and hydroxypropyl-beta-cyclodextrin were complexed bythe kneading method. Codeine laurate (0.700 g) andhydroxypropyl-beta-cyclodextrin (2.045 g) were blended together. Water(5 ml was added and the mixture ground together in a mortar with apestle to form a uniform paste. Grinding was continued for 30 minutes.The paste was then dried in a vacuum oven (40° C.; 0 bar) for 48 hours.The solid mass was broken up, passed through a 60 mesh screen andreturned to the vacuum oven (40° C.; 0 bar) for 12 hours in order toensure uniform drying of the complex. Analysis by HPLC for codeine basecontent, and Karl Fisher for moisture content gave the followingresults: % codeine base was 14.49%, and the moisture contents was 4.21%.The complex was characterised by DSC, FT-IR and XRD.

EXAMPLE 13

Codeine laurate and gamma-cyclodextrin were complexed by the kneadingmethod. Codeine laurate (0.700 g) and gamma-cyclodextrin (1.754 g) wereblended together. Water (2.5 mL) was added and the mixture groundtogether in a mortar with a pestle to form a uniform paste. Grinding wascontinued for 30 minutes. The paste was then dried in a vacuum oven (40°C.; 0 bar) for 48 hours. The solid mass was broken up, passed through a60 mesh screen and returned to the vacuum oven (40° C.; 0 bar) for 12hours in order to ensure uniform drying of the complex. Analysis by HPLCfor codeine base content, and Karl Fischer for moisture content gave thefollowing results: % codeine base was 16.08%, and the moisture contentwas 8.72%. The complex was characterised by DSC, FT-IR and XRD.

EXAMPLE 14

The unit composition of a sublingual tablet containing the equivalent of4 mg salbutamol base is as follows:

Salbutamol caprate gamma-CD complex (for Example 9) 32 mg Lactose NF 20mg Magnesium stearate 1 mg

The complex is blended with the lactose. The lubricant is blended andformed into sublingual tablets by compression at 10-30N.

EXAMPLE 15

Codeine laurate hydroxypropyl-beta-cyclodextrin complex from Example 12(1.352 g equivalent to 200 mg codeine base) is dissolved in purifieddeionised water (8 ml) buffered to pH 7.4 with phosphate buffer.Chlorhexidine gluconate (0.01%) is added. The volume is adjusted to 10ml by addition of phosphate buffer pH 7.4 and the tonicity of the finalsolution is adjusted with sodium chloride to 300 mOsm/kg. The solutionis filtered and filled into a metered dose nasal spray bottle. Each 0.25ml metered dose contains 5 mg codeine base suitable for nasaladministration.

EXAMPLE 16

The unit composition of a suppository containing the equivalent of 20 mgsumatriptan base is as follows:

Somatriptan caprate 32 mg Macrogol 6000 500 mg Macrogol 1540 300 mgMacrogol 400 200 mg

The macrogols ware heated to just above melting point. Finely dividedsumatriptan caprate is blended into the melt. The homogeneous liquidmass is poured into a mould.

EXAMPLE 17

Salbutamol laurate from Example 3 (15 mg equivalent to 8 mg salbutamolbase) is dissolved 0.5 ml of a mixture of propylene glycol (95%) andlaurocapram (5%). The resulting solution is filled into a reservoirtransdermal delivery system.

The physichochemical characteristics of several free bases, acidaddition salts and their cyclodextrin complexes are tabulated inTable 1. Melting points (peak onset temperature) were determined byDifferential Scanning Calorimetry using a Perkin Elmer DSC 7. Thesaturation solubilities were determined by shaking an excess of thecompound in phosphate buffer pH 7.4 at 25° C. The mixture was filtered(0.22(m) and the filtrate analysed by HPLC for drug content. The acidaddition salts are less soluble than the corresponding free bases. Thesolubility of the acid addition salts may be increased by cyclodextrincomplexation. Partition coefficients offer a prediction of the tendencyfor a drug to move from an aqueous compartment into a membrane, andconsequently have been found to correlate well with biological response[Pharmaceutical Codex 12th Edition, Pharmaceutical Press p 188]. Inorder to show that the acid addition salts possess improved membranepartitioning properties relative to the corresponding free bases, theapparent partition coefficients (Papp) were determined according to thefollowing method [Pharmaceutical Codex 12 Edition. Pharmaceutical Pressp70]:

Papp=P/(1+10^(pKa-pH))

where P=C_(o)/C_(w) and where C_(o) is the concentration of the drug inn-octanol and C_(w) is the concentration of the drug in phosphate bufferpH 7.4 at 25° C. Drug concentrations were determined by HPLC.

An increase in the apparent partition coefficient of the acid additionsalt relative to the corresponding free base is indicative of increasedlipophilicity which is related to rate of transfer of a molecule acrossa biological membrane. The results in Table 1 clearly illustrate thatthe acid addition salts of the invention possess higher apparentpartition coefficients relative to the corresponding free bases.

TABLE 1 MELTING POINTS AND EQUILIBRIUM SOLUBILITY DATA ON ACID ADDITIONSALTS Equilibrium solubility Compound Melting Point (° C.) (mg/ml)Sumatriptan base 169,0 2,342 Sumatriptan caprate 94,6 3,849 Salbutamolbase 148,8 16,663 Salbutamol caprate 99,4 3,820 Salbutamol laurate 104,04,245 Salbutamol Does not melt below 200 12,363 glycodeoxycholateCodeine base 152.7 10,574 Codeine laurate Does not melt below 200 5,227Sumatriptan caprate 88,8 4,333 HPBCD Sumatriptan caprate GDC 86,8 3,250Salbutamol caprate 91,0 4,107 HPBCD Salbutamol caprate GCD Does not meltbelow 200 1,865 Codeine laurate HPBCD Does not melt below 200 4,263Codeine laurate GCD Does not melt below 200 1,353

Melting point is given as onset value from DSC. If there is no endothermthen it is recorded as “does not melt below . . .” maximum temperatureof DSC run. Equilibrium solubility in phosphate buffer pH 7.4 (low ionicstrength) at 25° C.

TABLE 2 PARTITION COEFFICIENTS AND APPARENT PARTITION COEFFICIENTS FORACID ADDITION SALTS Apparent Partition Partition Compound CoefficientCoefficient Sumatriptan base 0,69 0,004039 Sumatriptan caprate 1,540.009015 Salbutamol base 0,42 0.005222 Salbutamol caprate 0,54 0,006714Salbutamol 0,61 0,007584 glycodeoxycholate

Apparent partition coefficient in phosphate buffer pH 7.4 and n-octanolat 25° C.

What is claimed is:
 1. A compound of formula I: B⁺RCOO⁻ wherein B⁺ is acation of a basic drug and RCOO⁻ is an anion of a bile acid, in solidisolated form.
 2. A compound according to claim 1, where B⁺ is a cationof a basic drug selected from the group consisting of codeine, morphine,fentanyl, naratriptan, zolmitriptan, rizatriptan, verapamil,nicardipine, captopril, enalapril, ramipril, metoclopramide, cyclizine,diphenoxylate, salmeterol, fenoterol, terbutaline, bupivacaine,lidocaine, procaine and dynorphin.
 3. A compound according to claim 1,wherein B⁺ is a cation of a basic drug selected from the groupconsisting of sumatriptan, salbutamol, codeine and loperamide.
 4. Acompound according to any one of the claims 1 to 3, wherein RCOO⁻ isglycodeoxycholate.
 5. A cyclodextrin inclusion complex comprises acompound of the formula I: B⁺RCCO⁻ wherein B⁺ is a cation of a basicdrug and RCOO⁻ is an anion of a bile acid, and an unsubstituted orsubstituted α, β or γ-cyclodextrin.
 6. A pharmaceutical compositionformulated for transdermal or transmucosal delivery comprising as anactive ingredient a compound of formula I: B⁺RCOO⁻ wherein B⁺ is acation of a basic drug and RCOO⁻ is an anion of a bile acid, the activeingredient being in solid, isolated form, together with one or moreexcipients for transdermal or transmucosal delivery.
 7. A pharmaceuticalcomposition formulated for transdermal or transmucosal deliverycomprising as an active ingredient a compound of formula I: B⁺RCOO⁻wherein B⁺ is a cation of a basic drug and RCOO⁻ is an anion of a bileacid, the active ingredient being in the form of a cyclodextrininclusion complex, together with one or more excipients for transdermalor transmucosal delivery.
 8. A pharmaceutical composition according toclaim 6 or 7, wherein B⁺ is a cation of a basic drug selected from thegroup consisting of codeine, morphine, fentanyl, naratriptan,zolmitriptan, rizatriptan, verapamil, nicardipine, captopril, enalapril,ramipril, metoclopramide, cyclizine, diphenoxylate, salmeterol,fenoterol, terbutaline, bupivacaine, lidocaine, procaine and dynorphin.9. A pharmaceutical composition according to claim 6 or 7 wherein B⁺ isa cation of a basic drug selected from the group consisting ofsumatriptan, salbutamol, codeine and loperamide.
 10. A pharmaceuticalcomposition according to claims 6 to 7, wherein RCOO⁻ isglycodeoxycholate.
 11. A pharmaceutical composition formulated fortransdermal or transmucosal delivery comprising as an active ingredienta compound selected from the group consisting of sumatriptan caprate,sumatriptan laurate, sumatriptan glycodeoxycholate, salbutamol laurate,salbutamol caprate, salbutamol glycodeoxycholate, codeine caprate,codeine laurate, loperamide glycodeoxycholate, sumatriptan capratecyclodextrin complex, salbutamol caprate cyclodextrin complex, andsalbutamol glycodeoxycholate cyclodextrin complex, together with one ormore excipients for transdermal or transmucosal delivery.
 12. Apharmaceutical composition according to claims 6 to 7, selected from thegroup consisting of a sublingual tablet, a nasal spray, a buccal tabletand a suppository.
 13. A pharmaceutical composition according to claims6 to 7, selected from the group consisting of a transdermal patch and atopical gel.